Gene expression is regulated in eukaryotic cells by the interplay of transcription factors. Steroid hormones (e.g., glucocorticoids, mineralocorticoids, estrogens, progestins, androgens and vitamin D) were found to bind to their nuclear receptors which are transcription factors and by this means regulate expression of gene coding for specific proteins and control critical cellular activities such as differentiation, proliferation and apoptosis (Meier, Recept. Signal Transduct. Res. 1997, 17, 319-335). The liver X receptors (LXRs) are a family of transcription factors that were first identified as orphan members of the nuclear receptor superfamily. The identification of a specific class of oxidized derivatives of cholesterol as ligands for the LXRs has been crucial to helping understand the function of these receptors in vivo and first suggested their role in the regulation of lipid metabolism. LXRs, members of the nuclear receptor super-family, include LXRα (also termed RLD-1) and ubiquitous receptor (UR, also called LXRβ). LXR-dependent pathways include but are not limited to cholesterol-7alpha-hydroxylase to increase the consumption of cholesterol via the bile acid route, expression of ABC proteins with the potential to stimulate reverse cholesterol transport and increase plasma HDL-C levels (Venkateswaran et al., J. Biol. Chem. 275, 2000, 14700-14707; Costet et al., J. Biol. Chem. 2000 275(36):28240-28245; Ordovas, Nutr. Rev. 58, 2000, 76-79, Schmitz and Kaminsky, Front. Biosci. 6, 2001, D505-D514), and/or inhibit intestinal cholesterol absorption (Mangelsdorf, XIIth International Symposium on Atherosclerosis, Stockholm, June 2000). In addition, possible cross talk between fatty acid and cholesterol metabolism mediated by liver LXR have been hypothesized (Tobin et al., Mol. Endocrinol. 14, 2000, 741-752).
In summary, ongoing research suggests that there exists complexity in LXR-dependent pathways and LXR variants may contribute to these pathways differently.
In order to understand the LXR-dependent pathways and mechanism of LXR action, it is important to isolate and characterize novel subtypes, variants, and/or isoforms of the LXR. Identification of the underlying LXR subtype, variant, or isoform responsible for a particular disease state or pathological condition can permit a more accurate means of prognosticating the LXR-related disease outcomes. Furthermore, the presence or amount of expression of such polynucleotides and/or the polypeptides encoded by such polynucleotides can be used for diagnosing associated pathological conditions, diagnosing a susceptibility to an associated pathological condition; develop gene-specific and isoform-specific therapies for diseases or disorders influenced by LXR, follow the progress of a therapy for an LXR-related disease or disorder, and/or develop new pharmaceutical drug targets.
With the recognition that these variants can be as critical to metabolic and physiologic function as proteins that are separately encoded, there is a need to identify and to characterize additional variants of the LXRα proteins. The present invention satisfies this need and provides related advantages as well.